BioFe Mechanism of Action for the treatment of iron deficiency anemia

BioFe 治疗缺铁性贫血的作用机制

基本信息

批准号：
10009565
负责人：
Darren Wolfe
金额：
$ 30万
依托单位：
SIDERO BIOSCIENCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10009565
关键词：
Address Anemia Anemia due to Chronic Disorder Animal Model Apical Binding Biological Biological Availability Biological Sciences Biology Blood Blood Circulation Caco-2 Cells Carrier Proteins Cells Characteristics Child Chronic Clinical Clinical Data Clinical Trials Complex Consumption Data Dietary Iron Disease Distress Dried Yeast Elderly Electron Microscopy Enterocytes FTH1 gene Female of child bearing age Ferritin Ferrous Sulfate Funding H ferritin Health Human Human Milk Immunoglobulin Domain Individual Infant Infection Inflammation Inflammatory Inflammatory Response International Intestines Intravenous Iron Iron deficiency anemia Knowledge L-ferritin Laboratories Letters Malnutrition Marketing Meat Mediating Mediation Membrane Methods Nursing infant Nutrition Disorders Oral Outcome Study Pathway interactions Performance Phase Placebos Plant Roots Plants Positioning Attribute Probiotics Process Protein Export Pathway Proteins Regulation Reporting Risk Rodent Salts Serum Site Small Business Innovation Research Grant Small Business Technology Transfer Research Source Stomach Surface T-Lymphocyte Technology Testing Therapeutic Time Tissues Toxic effect Woman Yeasts absorption age group apical membrane base basolateral membrane divalent metal evidence base gastrointestinal gut microbiome gut microbiota hepcidin indexing interest intestinal epithelium iron absorption iron deficiency iron supplement medical food metal transporting protein 1 nanoparticle nonhuman primate novel oral supplementation pathogen pre-clinical prevent receptor response side effect standard of care success treatment comparison uptake

项目摘要

Iron deficiency (ID) is the most common and widespread nutritional disorder worldwide with over 2 billion people suffering significant negative health effects. There is a widespread, serious misperception that oral iron supplements are safe and effective at alleviating ID; yet in a recent Cochrane review of 67 clinical trials, women taking oral iron supplements had just a 38% decreased risk of ID at the end of treatment compared to placebo. Moreover, these subjects had a 114% increased risk of side effects, the vast majority of which were associated with gastrointestinal (GI) disturbance. The current standard of care for treating ID involves iron salts or more recently iron nanoparticles which are degraded in the stomach and release elemental iron. SideroBiosciences has developed a disruptive technology consisting of nutritional yeast modified to express a H-ferritin:iron complex known as BioFe. The concept of using an H- ferritin;iron complex is rooted in mimicking iron delivery from breast milk and using nutritional yeast provides an easily accessible and economical platform for marketing and consumption by many different cultures and age groups. That the ferritin:iron complex in BioFe is specifically H- ferritin distinguishes it from L-ferritin or plant ferritin, both of which have had limited success as iron supplements because they are degraded in the gut to release the iron and thus use the same pathway into enterocytes as iron salts and thus their performance is at best similar to the iron salts. BioFe has been successfully tested in rodents, non-human primates and humans (including a STTR funded study). While the absorption and secretion of elemental iron across the membranes of intestinal enterocytes are relatively well described, the receptor(s), transporter(s), and regulatory mechanism(s) for H-Ferritin:Iron complexes have not been described. In multiple discussions with potential marketing partners, SideroBiosciences has been consistently queried for more details on how the entry of the ferritin;iron complex into the body are different from iron salts. Therefore,to address these questions, we have provided exciting pilot data to pursue in this application that will interrogate mechanisms by which Ferritin:Iron complexes are transported across the apical membrane of intestinal enterocytes, processed within the intestinal cells, and secreted across the basolateral membrane into the systemic circulation. Furthermore, because the mechanism of release from the enterocyte is different from elemental iron BioFe will be tested for its ability to treat inflammatory mediated iron deficiency in rodents to position itself to be clinically tested in individuals with ID resulting from chronic inflammation which is a significant clinical problem that BioFe can address.

缺铁（ID）是世界范围内最常见和最广泛的营养失调症，超过 20 亿人的健康受到严重负面影响。存在着广泛而严重的错误地认为口服铁补充剂对于缓解智力障碍是安全有效的；然而在最近的一次 Cochrane 审查了 67 项临床试验，服用口服铁补充剂的女性仅有 38% 与安慰剂相比，治疗结束时 ID 的风险降低。此外，这些受试者还副作用风险增加 114%，其中绝大多数与胃肠道（GI）紊乱。目前治疗智力障碍的护理标准涉及铁盐或者最近的铁纳米颗粒在胃中降解并释放元素铁。 SideroBiosciences 开发了一种由营养酵母组成的颠覆性技术修饰后可表达 H-铁蛋白：铁复合物（称为 BioFe）。使用 H 的概念铁蛋白；铁复合物的根源在于模仿母乳中的铁输送并使用营养酵母为营销和消费提供了一个易于访问且经济的平台许多不同的文化和年龄组。 BioFe 中的铁蛋白：铁复合物特别是 H- 铁蛋白与 L-铁蛋白或植物铁蛋白不同，后两者都取得了有限的成功，因为铁补充剂，因为它们在肠道中降解以释放铁，从而使用与铁盐进入肠细胞的途径相同，因此它们的性能至多类似于铁盐。 BioFe 已在啮齿动物、非人类灵长类动物和人类身上进行了成功测试（包括 STTR 资助的研究）。同时元素铁的吸收和分泌肠细胞膜的描述相对较好，受体， H-铁蛋白的转运蛋白和调节机制：铁复合物尚未被研究描述的。在与潜在营销合作伙伴的多次讨论中，SideroBiosciences 已不断询问有关铁蛋白如何进入铁复合物的更多详细信息身体与铁盐不同。因此，为了解决这些问题，我们提供了在此应用程序中追求令人兴奋的试点数据，该数据将询问机制铁蛋白：铁复合物穿过肠肠上皮细胞的顶膜运输，在肠细胞内加工，并穿过基底外侧膜分泌到体循环。此外，由于肠上皮细胞的释放机制是与元素铁不同，BioFe 将测试其治疗炎症介导的能力啮齿类动物缺铁，以便在患有 ID 的个体中进行临床测试慢性炎症是 BioFe 可以解决的一个重要临床问题。